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5jfr

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Potent, Reversible MetAP2 Inhibitors via Fragment Based Drug Discovery

Structural highlights

5jfr is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.6Å
Ligands:	, , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

MAP2_HUMAN Cotranslationally removes the N-terminal methionine from nascent proteins. The N-terminal methionine is often cleaved when the second residue in the primary sequence is small and uncharged (Met-Ala-, Cys, Gly, Pro, Ser, Thr, or Val). The catalytic activity of human METAP2 toward Met-Val peptides is consistently two orders of magnitude higher than that of METAP1, suggesting that it is responsible for processing proteins containing N-terminal Met-Val and Met-Thr sequences in vivo. Protects eukaryotic initiation factor EIF2S1 from translation-inhibiting phosphorylation by inhibitory kinases such as EIF2AK2/PKR and EIF2AK1/HCR. Plays a critical role in the regulation of protein synthesis.

Publication Abstract from PubMed

Methionine aminopeptidase-2 (MetAP2) is an enzyme that cleaves an N-terminal methionine residue from a number of newly synthesized proteins. This step is required before they will fold or function correctly. Pre-clinical and clinical studies with a MetAP2 inhibitor suggest that they could be used as a novel treatment for obesity. Herein we describe the discovery of a series of pyrazolo[4,3-b]indoles as reversible MetAP2 inhibitors. A fragment-based drug discovery (FBDD) approach was used, beginning with the screening of fragment libraries to generate hits with high ligand-efficiency (LE). An indazole core was selected for further elaboration, guided by structural information. SAR from the indazole series led to the design of a pyrazolo[4,3-b]indole core and accelerated knowledge-based fragment growth resulted in potent and efficient MetAP2 inhibitors, which have shown robust and sustainable body weight loss in DIO mice when dosed orally.

Discovery of potent, reversible MetAP2 inhibitors via fragment based drug discovery and structure based drug design-Part 2.,McBride C, Cheruvallath Z, Komandla M, Tang M, Farrell P, Lawson JD, Vanderpool D, Wu Y, Dougan DR, Plonowski A, Holub C, Larson C Bioorg Med Chem Lett. 2016 Jun 15;26(12):2779-83. doi:, 10.1016/j.bmcl.2016.04.072. Epub 2016 Apr 25. PMID:27136719^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ McBride C, Cheruvallath Z, Komandla M, Tang M, Farrell P, Lawson JD, Vanderpool D, Wu Y, Dougan DR, Plonowski A, Holub C, Larson C. Discovery of potent, reversible MetAP2 inhibitors via fragment based drug discovery and structure based drug design-Part 2. Bioorg Med Chem Lett. 2016 Jun 15;26(12):2779-83. doi:, 10.1016/j.bmcl.2016.04.072. Epub 2016 Apr 25. PMID:27136719 doi:http://dx.doi.org/10.1016/j.bmcl.2016.04.072